The aldol and related carbonyl addition reactions have long been among the cornerstones of synthetic organic chemistry. The products derived from these reactions (1,3-dioxygenated compounds) have a special importance because of their widespread occurrence in natural products and their use in the further synthetic manipulations. Until recently, all such 1,3-dioxygenated molecules have been prepared by the basic carbonyl addition strategy or one of its many modern variations. The specific aim of the grant is to provide the first general alternative to this carbonyl addition strategy. Our route, termed the cycloadditive strategy because of the nature of the carbon-carbon bond forming reaction, involves olefin-nitrile oxide dipolar cycloaddition and reductive conversion of the resulting heterocycle to a 1,3-dioxygenated product. During the first granting period, the key aforementioned reductive transposition has been developed and is now well established. The main objective is now to develop the cycloadditive strategy in parallel to the powerful carbonyl addition strategy to provide a synthetic complement for the first time. Proposals to control the selectivity of the cycloaddition reaction based on new methods of nitrile oxide generation are outlined. In addition, new methods to control both absolute and relative stereochemistry are emphasized. Synthetic targets designed to illustrate the new chemistry are selected for biomedical relevance and include sesbanimide (antitumor), the pyranonaphthoquinones (antitumor/antibiotic) and the iridoids.